The treatment for hormone receptor-positive breast cancer includes therapies designed to block estrogen action. Although these therapies have changed the natural history of hormone-dependent breast cancer, many tumors exhibit ofe novo or acquired endocrine resistance. Studies with human breast cancer cell lines as well as molecular profiling of primary mammary tumors have identified molecular alterations associated with hormonal independence and drug resistance. One of these mechanisms is overexpression of the HER2 (ErbB2) protooncogene and its signaling network. Overexpression of HER2 is the only mechanism of antiestrogen resistance for which prospective clinical data exist. However, only <10% of hormone-dependent breast cancer express high levels of HER2, suggesting that for the majority of hormone-receptor positive breast cancers, mechanisms of escape from endocrine therapy remain to be discovered. In addition to the substantial improvements of antiestrogen therapy, assays have been developed to predict the odds of benefit from it. These assays do not identify the molecular alteration causally associated with treatment failure and tumor recurrence. More recently, cancer cell proliferation as measured by Ki67 immunohistochemistry in the tumor specimen after neoadjuvant hormonal therapy has been shown to correlate with disease-free and overall survival. These data suggest that pharmacodynamic biomarkers of the cellular and molecular effects of endocrine therapy in the breast tumor, likely because they incorporate the effects of therapy, can be used to identify cancers that are highly hormone-dependent and thus sensitive to endocrine treatment vs. those that are cfe novo resistant and/or destined to recur faster. We hypothesize that those tumors exhibiting a marked inhibition of cell proliferation are likely to do well on adjuvant hormonal therapy alone whereas those that do not, are destined to an early recurrence. To 1) determine if inhibition of HER2 function reverses resistance to endocrine therapy, and 2) discover novel mechanisms associated with resistance to endocrine therapy in hormone receptor-positive tumors without HER2 overexpression, we propose the following aims: Aim 1: To determine if combined neoadjuvant therapy with the aromatase inhibitor letrozole and the HER2 tyrosine kinase inhibitor lapatinib induces pathologic complete responses in hormone receptor-positive breast cancers that overexpress HER2 and establish biomarkers predictive of response to this therapy. Aim 2: To determine if the post-letrozole Ki67 in hormone receptor-positive/HER2-negative tumors mirrors the recurrence score as measured by RT-PCR of 21 selected genes in formalin-fixed tumor tissue sections and to use these biomarkers to discover gene expression signatures associated with hormonal dependence. Aim 3: To determine the mechanisms by which loss of PTEN in hormone receptor-positive breast cancer cells dysregulates phosphatidylinositol-3 kinase (PI3K) signaling and generates resistance to antiestrogens.